Macrocyclic amines (e.g., cyclam) readily form complexes in high yields with Tc-99m. Due to the ease of formation and the extraordinary stability of these complexes, the potential of these ligands as Tc-99m-radiopharmaceuticals appears to be exceptional. The chemistry of Tc-99m complexation with cyclam has been, to a large extent, elucidated and the complexation techniques refined in our laboratory. This progress and continuing studies provide a firm foundation that will be used to systematically design and formulate new Tc-99m macrocyclic amine complexes that should be useful for imaging studies in Nuclear Medicine. The three basic objectives of this research are to: (1) synthesize derivatized forms of cyclam that can be used as cationic-hepatobiliary imaging agents when they are complexed with Tc-99m; (2) prepare bifunctional-chelating agents, by adding side chains to cyclam that will conjugate cyclam to antibodies; and (3) develop a new macrocyclic amine ligand that will form a stable, lipophilic complex with reduced Tc-99m. Our initial efforts will focus on the development of synthetic methods to attach various side chains to cyclam and on the synthesis of new macrocyclic amines. As these methods are develped, they should supply us with derivatives that meet the objectives and their radiopharmacology will be assessed by "in vivo" and "in vitro" techniques. As an example, by adding different substituents to cyclam derivatives, Tc-99m-hepatobiliary imaging agents will be formed and their rate of blood clearance by the liver will be measured in rabbits and dogs. Similarly, we will compare the effects of cyclam conjugation of HSA-Antibodies with respect to their antigen binding affinity (by affinity chromotography) and their rate of blood clearance in dogs. This will permit us to determine the optimum balance between the increase in blood clearance rate and the decrease in the antibody activity of the conjugates. If successful in our synthesis of a new macrocyclic amine ligand that forms a neutral-lipophilic complex with Tc-99m, the binding affinity of these complexes to plasma proteins, the octanol/H2O partition co-efficients and their effectiveness as a brain-blood flow agent will be assessed.